The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.
“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator, of Memorial Sloan Kettering Cancer Center, New York.
“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (
The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.
By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).
The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.
At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).
In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.
The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).
Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.
Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.
The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.
“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.
“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.
“This study is one of the most important in the last 5 years,” commented session cochair, of the Columbia University Irving Medical Center, New York.
Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.
Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”
The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.